1. Field of the Invention
The present invention relates to a composition for accelerating secretion of estrogen and regenerating tissue cells of female sexual organs and a method for treating or preventing a disease, disorder or symptom associated with menopause.
2. Description of the Related Art
A hormone secreted from follicles in ovaries, estrogen, develops sexual organs and makes them functional to exhibit the secondary sexual character and accelerate the development of uterus, the growth of endometrium, the development of mammary gland and regular menstruation. In addition to ovaries, estrogen is secreted from placenta, adrenal cortex and testis in a small amount. Three types of steroids, estrone, estradiol and estriol found in body are known.
Estrogen is produced from androgenic precursors through an enzymatic process, aromatization. 17 beta-estradiol (E2), a strong estrogen, which exists predominantly in premenopausal women is synthesized during the formation of follicle, is secreted to blood stream and bound to sex hormone binding globulin in a portion, and then circulates to cells in body. The main metabolic pathway of estradiol is to be oxidized reversibly to estrone, a weak estrogen and finally converted to estriol (E3). Estrone is produced by aromatization of androstenedione, precursor of androgen, in the peripheral tissue. The above compounds are metabolized to form sulfate and glucuronide and excreted (Lievertz R W. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156:1289-1293(1987)). As aromatization occurs in adipose tissue, those who have many adipose tissues have more estrogen. Estradiol and estrone may be metabolized in liver to estriol, very weak estrogen (Anderson F. Kinetics and pharmacology of estrogens in pre- and postmenopausal women. Int J Fertil 38 (suppl 1):53-64 (1993)). Other estrogen metabolites as well as estradiol and estrone could function like estrogen. Therefore, it could be understood that the systematic estrogen effects in women depends on both estrogen and its metabolites.
The average concentrations of estradiol and estrone are 520 pg/ml and 3,070 pg/ml respectively. The peak concentrations of estradiol and estrone are 200-400 pg/ml and 170-200 pg/ml respectively in ovulation phase and decrease to the minimum concentrations of 40-60 pg/ml and 40-60 pg/ml respectively in the early stage of menstruation.
The ratio of estradiol to estrone in premenopause is generally lager than 1 (Odonnell M B. Pharmacokinetic and pharmacologic variation between different estrogen products. J Clin Pharmacol 35 (suppl):18S-24S (1995)). In postmenopause, estrone produced by conversion of adrenal androstenedione becomes a major estrogen.
The metabolic pathway including 2-hydroxyation is more complicated and results in the formation of catecholesterogen. This pathway is more important in the central nervous system such as brain than in the peripheral tissue. Estrogen exhibits its effects by modification of catecholamine metabolite (Lievertz R W. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156:1289-1293(1987)). Since catecholamine interacts with dophamin (a precursor of adrenalin) receptor, alpha 1-adrenalin receptor and serotonin receptor, it is considered to be important. Furthermore, the hydroxy derivatives of estrogen play other roles. For example, 4-hydroxy estrogen functions like estrogen; however, 2-hydoxy estrogen does not. However, 2-hydroxy derivatives of estradiol functions not only like estrogen, but also catecholamine (Lievertz R W. Pharmacology and pharmacokinetics of estrogen. Am J Obstet Gynecol 156:1289-1293(1987)). This accounts partially for the mechanism how estrogen has an effect on the central nervous system.
The main physiological functions of estrogn is to regulate the development, differentiation and action of sexual tissues including mammary gland, uterus and ovaries (Kuiper G G J M, Carlsson B, Grandien K, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138:863-870(1997)). Estrogne stimulates the growth of endometrium, myometrium, vagina and urethral epithelium. Estrogen also functions in the smooth flow of blood in sexual tissues, the increase of secretion in uterine gland and induces the expression of progesterone and luteinzing hormone receptor. Estrogen has an effect on the growth and development of backbone, fat distribution in women and lipid metabolite as well as female sexual organs and the secondary sexual character. Estrogen plays roles in skin, collagen tissue, neuron and cardiovascular system.
Estrogen deficiency brings up the symptoms such as hot flashes caused from vasomotor instability and in the long term, urogenital degeneration, osteoporosis, tooth loss, arteriosclerosis and coronary heart disease, etc., occasionally resulting in dementia (Maddox R W, Carson D S, Barnes C L. Estrogens and postmenopausal women. US Pharmacist 23:141-150(1998); and Guyton A C, Hall J E. Textbook of Medical Physiology. 9th ed. Philadelphia: W. B. Saunders, 1996).
In postmenopause, women experience various menopausal symptoms such as blushing and depression caused from the decreased estrogen secretion in function-deteriorated ovarian. For a hormone replacement therapy, the postmenopausal women lack of estrogen is administered with extrinsic estrogen to reduce the risk of disease occurrence.
Administering estrogen into postmenopausal women improves vasomotion and urogenital diseases, protects and controls osteoporosis and reduces the risk of coronary heart disease (Maddox R W, Carson D S, Barnes C L. Estrogens and postmenopausal women. US Pharmacist 23:141-150(1998)).
However, the problem is that such a hormone replacement therapy may increase the activity of cancer-inducing gene, leading to increased incidence rate of breast cancer and metrocarcinoma, etc.
The known estrogen-replacing agents are artificially synthesized or available from natural source. For example, premarin made from horse urine increases the concentration of estradiol and estrone up to that in secretion phase (Stumpf P G. Pharmacokinetics of estrogen. Obstet Gynecol 75 (suppl):9S-14S(1990)). However, as the source of the product is horse urine, the patient compliance is far poor.
As the example of plant products, mexico yam contains steroid precursor used for synthesizing esterified-estrogen (estrogen sodium salt mixture comprised of estrone 75%-85% and equiline 6%-15% as main components) (e.g., estratab, Menest). Such plants as soy bean, date palm and pomegranate contain nonsteroid plant compound, phytoestrogen. Natural estroen originated from these plant functions as agonists and/or antagonist (Barrett J. Phytoestrogens: friends or foes? Environ Health Perspect 104:478-482(1996)).
17 beta-estradiol, estrone, estrogen sulfate are the exmples of chemically modified estrogen. Such synthesized estrogen is used generally as an oral contraceptive, but hardly in hormone replacement therapy.
In short, the amount of estrogen secreted decreases with aging and the pattern of estrogen secretion is directly related to the advancement of aging. It has been recognized in the art that the administration of hormone replacement therapy allows to improve the usual symptoms of menopause, while the conventional hormone replacement therapy gives rise to severe adverse-effects.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.